Process for the preparation of acid halides

ABSTRACT

A process for the preparation of acid halides of formula I 
     
       
         
         
             
             
         
       
     
     which are useful as intermediates in the preparation of i.a. pharmaceutically active compounds.

PRIORITY TO RELATED APPLICATION(S)

This application is a continuation of application Ser. No. 12/105,339, filed Apr. 18, 2008, which claims the benefit of European Patent Application No. 07106893.6, filed Apr. 25, 2007. The entire contents of the above-identified applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention is directed to a process for the preparation of acid halides which are useful as intermediates in the preparation of pharmaceutically active compounds, and in particular, for the preparation of compounds that inhibit cholesterylester transfer protein (CETP) such as those as described in EP 1,020,439. CETP is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between lipoproteins. It has been demonstrated that the inhibition of CETP increases the levels of high density lipoprotein (HDL).

U.S. Patent Application Publication No. 2007/0100154, discloses a “Process for the Preparation of Acid Chlorides” also useful as intermediates in the preparation of CETP inhibitors.

SUMMARY OF THE INVENTION

The present invention provides an improved production process for intermediates in the preparation of pharmaceutically active compounds and, in particular, for the preparation of intermediates used in the preparation of CETP inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the present invention provides a process for the preparation of a compound of formula I

wherein:

-   R¹ is hydrogen, C₁-C₈alkyl or C₂-C₈alkenyl which are unsubstituted     or substituted by one or more substituents selected from C₁-C₈alkoxy     and C₃-C₈cycloalkyl; and -   R² and R³ are combined with the carbon atom to which they are     attached to form C₃-C₇-cycloalkyl or C₅-C₈cycloalkenyl;     comprising reacting a compound of formula II

wherein R¹, R² and R³ have the above meanings; with thionylchloride in the presence of a tri-C₁-C₅alkylamine and an aliphatic hydrocarbon solvent.

The compounds of formula I may be used as intermediates in the synthesis of valuable pharmaceutical compounds, e.g. those as described in e.g. EP 1,020,439.

Accordingly, in another embodiment the present invention provides a process comprising the synthetic steps represented in the following scheme:

wherein R¹, R² and R³ are as defined above and R⁴ is C₁-C₈alkyl. In particular, the process comprises reacting a compound of formula I with bis(2-aminophenyl)disulfide to acylate the amino groups of the (2-aminophenyl)disulfide, reducing the amino-acylated disulfide product with a reducing agent such as triphenylphosphine, zinc or sodium borohydride to yield the thiol product, and acylating the thiol group in the thiol product with R⁴C(O)Cl.

The additional steps may be performed, e.g., according to the procedures described in Shinkai et al., J. Med. Chem. 43:3566-3572 (2000).

Examples for C₁-C₈alkyl include methyl, ethyl, straight and branched propyl, butyl, pentyl, hexyl, e.g. CH₂CH(CH₂CH₃)₂, heptyl and octyl. For R¹, C₁-C₈alkyl is preferably CH₂CH(CH₂CH₃)₂. For R⁴, C₁-C₈alkyl is preferably isopropyl.

Examples for C₂-C₈alkenyl include unsaturated carbon chains containing one or more double bonds at any possible position, e.g. vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.

Examples for C₃-C₇cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred is e.g. cyclohexyl. Examples for C₅-C₈cycloalkenyl include cyclo-pentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl and cyclooctadienyl. Preferred are cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “tri-C₁-C₅alkylamine” denotes a compound of formula R⁴N(R⁵)R⁶ wherein R⁴, R⁵ and R⁶ independently are a C₁-C₈alkyl, and includes triethylamine, tributylamine, di-ethyl-methylamine, dimethyl-ethylamine and methylethylbutylamine.

The term “aliphatic hydrocarbon” refers to a branched, straight or cyclic hydrocarbon chain, such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, or mixtures thereof. The most preferred aliphatic hydrocarbon is heptane.

The process may take place at a temperature in the range from 20 to 60° C., e.g. in a range from 40 to 55° C.

The acylating steps of the present invention are preferably conducted in the presence of a base. Preferred bases include organic bases with N-Methylmorpholine being a preferred organic base.

The amount of thionylchloride in relation to the compound of formula II, in the reaction mixture may be in the range from 1.0 to 2.0 equivalents of thionylchloride, e.g. from 1.0 to 1.2 equivalents, e.g. 1.2 equivalents.

The amount of the tri-C₁-C₅alkylamine in relation to the amount of the compound of formula II may be at a ratio of from 5 mol % to 0.1 mol %, e.g. from 0.3 mol % to 0.5 mol %, e.g. 0.3 mol %.

In another aspect the present invention provides a process for the preparation of a compound of formula I as above, comprising reacting a compound of formula II as above in the presence of a tri-C₁-C₅alkylamine and an aliphatic hydrocarbon solvent by continuously adding thionylchloride.

The term “continuously adding” denotes the addition of thionylchloride to a solution of compound II in an aliphatic hydrocarbon solvent, during a period of time from 10 minutes to 5 hours, depending on the batch size. The solution of compound II is heated to the desired temperature prior to the addition of thionylchloride. This method is different from the batch mode where all components are mixed at RT and the mixture is heated to the desired temperature.

In one embodiment the present invention provides a process for the preparation of a compound of formula I wherein R¹ is —CH₂CH(CH₂CH₃)₂. In another embodiment the present invention provides a process for the preparation of a compound of formula I wherein the tri-C₁-C₅alkylamine is triethylamine or tributylamine. In a preferred embodiment the present invention provides a process for the preparation of a compound of formula I wherein the tri-C₁-C₅alkylamine is tributylamine. When using tributylamine no precipitation of the hydrochloride salt of the tertiary amine occurs.

The compounds of formula II are commercially available or can be prepared by procedures known to the skilled person.

In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS version 2.2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

Example Preparation of 1-(2-Ethyl-butyl)-cyclohexanecarbonyl Chloride in the Presence of 0.003 Eq. Tributylamine and Heptane as the Solvent

A mixture of 6.0 kg (28.3 mol) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and 20.6 mL tributylamine (0.085 mmol) in 10 L heptane was warmed to 50° C. 2.5 L (34.5 mol) of thionyl chloride was added during 40 minutes at a temperature of 40-50° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 53-55° C. An IPC-control after 60 minutes indicated complete conversion (0.04% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components under reduced pressure (70° C. bath, 13-8 mbar) 6.86 kg of the residue was obtained (assay 92.5% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 97.2%) 

1. A process for the preparation of a compound of formula I:

wherein: R¹ is selected from the group consisting of: (1) hydrogen, (2) C₁-C₈alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of C₁-C₈alkoxy and C₃-C₈cycloalkyl, and (3) C₂-C₈alkenyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of C₁-C₈alkoxy and C₃-C₈cycloalkyl; and R² and R³ are combined with the carbon atom to which they are attached to form C₃-C₇cycloalkyl or C₅-C₈cycloalkenyl; comprising reacting a compound of formula II:

wherein R¹, R² and R³ have the above meanings; with thionylchloride in the presence of a tri-C₁-C₅alkylamine and an aliphatic hydrocarbon solvent.
 2. The process according to claim 1 additionally comprising the step of acylating a compound of the formula III:

with a compound of formula I to yield a compound of formula IV:

wherein R¹, R² and R³ are as defined in claim
 1. 3. The process according to claim 2 additionally comprising the step of reducing the compound of formula IV with a reducing agent to yield a compound of formula V:

wherein R¹, R² and R³ are as defined in claim
 1. 4. The process according to claim 3 additionally comprising the step of acylating the compound of formula V with R⁴C(O)Cl to yield a compound of formula VI:

wherein R¹, R² and R³ are as defined in claim 1 and R⁴ is C₁-C₈alkyl.
 5. The process according to claim 4 wherein R⁴ is isopropyl.
 6. The process according to claim 1 wherein the thionyl chloride is present in the range from 1.0 to 2.0 equivalents of thionylchloride in relation to the compound of formula II.
 7. The process according to claim 1 wherein the amount of the tri-C₁-C₅alkylamine in relation to the amount of the compound of formula II is at a ratio of from 5 mol % to 0.1 mol %.
 8. The process according to claim 1 wherein thionylchloride is continuously added.
 9. The process according to claim 1 wherein in formula I R² and R³ are combined with the carbon atom to which they are attached to form C₃-C₇cycloalkyl.
 10. The process according to claim 1 wherein in formula I, R¹ is CH₂CH(CH₂CH₃)₂ and R² and R³ are combined with the carbon atom to which they are attached to form cyclohexyl.
 11. The process according to claim 1 wherein the tri-C₁-C₅alkylamine is triethylamine or tributylamine.
 12. The process according to claim 1 wherein the tri-C₁-C₅alkylamine is tributylamine.
 13. The process according to claim 2 wherein the acylating steps are performed in the presence of a base.
 14. The process according to claim 13 wherein the base is an organic base.
 15. The process according to claim 14 wherein the organic base is N-methylmorpholine. 